Cardiac and cardiovascular diseases, such as ventricular hypertrophy, coronary artery disease, essential hypertension, acute hypertensive emergency, cardiomyopathy, heart insufficiency, exercise tolerance, chronic heart failure, arrhythmia, cardiac dysrhythmia, syncopy, arteriosclerosis, mild chronic heart failure, angina pectoris, cardiac bypass reocclusion, intermittent claudication (arteriosclerosis oblitterens), diastolic dysfunction and systolic dysfunction, are among the most common causes of death in the industrialized world.
During ischemia, the myocardial metabolism changes from utilisation of short chain free fatty acids and lactate under normoxic conditions to primarily breakdown of intracellular glycogen and anaerobic glycolysis causing net production of lactate and lowering of interstitial pH. The dramatic pH reduction within the myocardium following a total coronary artery occlusion causes profound changes in the cardiac electric conduction system and ion-channel function within the myocytes. These changes all in all lead to development of arrhythmia; particularly ventricular fibrillation which is in most cases fatal for the patient, unless acute intervention (defibrillation) and pharmacological treatment of the arrhythmia is initiated immediately after the onset. There is thus a pressing need for drugs which may help in reducing the mortality of such diseases.
Clinical accepted anti-arrhythmic agents exert their effect via interaction with ion channels in the myocardial conducting and/or contracting cells or by interference with beta-adrenoceptors. (2R, 3R, 4R)-3,4-dihydroxy-2-hydroxymethylpyrrolidine and related compounds are selective glycogen-phosphorylase inhibitors and are disclosed in WO97/09040 to Novo Nordisk A/S for the treatment of type 2 diabetes. WO 95/24391 and WO01/23347 to Novo Nordisk A/S discloses other groups of glycogen-phosphorylase inhibitors, which may be used for the treatment of type 2 diabetes. These compounds have not been associated with interference with the electric conduction system of the heart and are as such not associated with arrhythmic potential or other cardiovascular effects as the other known anti-arrhythmic agents used in clinical therapy today, such as lidocaine, amiodarone, sotalol and others Class I-IV anti-arrhythmic drugs.
WO96/39384 to Pfizer, Inc. concerns the use of a class of glycogen phosphorylase inhibitors for treating hyperglycaemia, diabetes, hypercholesterolaemia, atherosclerosis, hyperinsulinaemia, hypertension, hyperlipidaemia and myocardial ischemia.
Patent application EP 1125580 to Pfizer, Inc. concerns methods of treating specifically diabetic cardiomyopathy comprising administration of a therapeutically effective amount of a glycogen phosphorylase inhibitor to a patient having or at risk of having diabetic cardiomyopathy.
Patent application EP0846464 to Pfizer, Inc. concerns the use of a glycogen phosphorylase inhibitor for the manufacture of a medicament for reducing non-cardiac tissue damage resulting from ischemia or hypoxia.